Targeting netrin-3 in small cell lung cancer and neuroblastoma.

Animals Humans Lung Neoplasms Netrin-1 Netrins Neuroblastoma Small Cell Lung Carcinoma

axon guidance netrin-1 netrin-3 neuroblastoma small cell lung cancer

Journal

EMBO molecular medicine

ISSN: 1757-4684

Titre abrégé: EMBO Mol Med

Pays: England

ID NLM: 101487380

Informations de publication

Date de publication:
09 04 2021

Historique:

revised: 01 02 2021

received: 04 06 2020

accepted: 07 02 2021

pubmed: 16 3 2021

medline: 26 10 2021

entrez: 15 3 2021

Statut: ppublish

Résumé

The navigation cue netrin-1 is well-documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin-1. Interestingly, the epitope recognized by NP137 in netrin-1 shares 90% homology with its counterpart in netrin-3, the closest member to netrin-1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin-3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin-3 and netrin-1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL-1 or NeuroD1 transcription factors in SCLC. Netrin-3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin-3 for netrin-1 receptors and we demonstrated that netrin-3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin-3 in NB and SCLC.

Identifiants

DOI: 10.15252/emmm.202012878 PMID: 33719214 PMC: PMC8033513

pubmed: 33719214

doi: 10.15252/emmm.202012878

pmc: PMC8033513

doi:

Substances chimiques

Netrins 0

netrin-3 0

Netrin-1 158651-98-0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

e12878

Informations de copyright

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